Φαινόμενο μη επαναρροής (no reflow phenomenon)

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1 Φαινόμενο μη επαναρροής (no reflow phenomenon) Αθηνόδωρος Ν. Νικητόπουλος Επεμβατικός Καρδιολόγος Επιστημονικός Συνεργάτης Β ΚΚ ΑΠΘ Ιατρικό Διαβαλκανικό Κέντρο

2 Δεν έχω να δηλώσω κάποια αντίθεση συμφερόντων σχετικά με την παρούσα ομιλία

3 Φαινόμενο μη επαναροής (No Reflow phenomenon) Μια δραματική εξέλιξη της επαναγγείωσης ενός στεφανιαίου αγγείου

4 Ορισμός Αποτελεί το φαινόμενο κατά το οποίο υπάρχει υποαιμάτωση τμήματος του μυοκαρδίου, παρόλη την παρουσία βατών επικαρδιακών αρτηριών

5 Historical perspective The first clinical observation of coronary no-reflow was reported by Schofer et al.in In 1989, Wilson et al. observed persistent angina with ST elevation in association with a slow angiographic antegrade flow despite a widely patent angioplasty site in five patients immediately after PTCA of a thrombus containing lesion. In 1991,Pomerantz et al. reported five more cases of noreflow successfully treated by intracoronary verapamil. The first clinical case of no-reflow during PTCA for acute myocardial infarction was reported by Feld et al. in 1992.

6 Επίπτωση INCIDENCE OF ANGIOGRAPHIC NO-REFLOW IN VARIOUS PCI SETTINGS All PCI 0.6% 2% Primary PCI 8.8% 11.5% SVG PCI 8% 40% Rotational atherectomy Upto 16% Jaffe et al. MVO and Mechanisms. Circualtion Jaffe et al. Prevention and treatment of no reflow. JACC 2010.

7 Επίπτωση στο STEMI Ποικίλει μεταξύ 5-50% των περιπτώσεων PPCI, ανάλογα με τη μέθοδο εκτίμησης

8 THROMBOLYSIS IN MYOCARDIAL INFARCTION FLOW GRADING SYSTEM DEFINED Thrombolysis in Myocardial Infarction Flow Grading System Grade 0 Grade 1 Grade 2 Grade 3 Complete occlusion of the infarct-related artery Some penetration of contrast material beyond the point of obstruction but without perfusion of the distal coronary bed Perfusion of the entire infarct vessel into the distal bed but with delayed flow when compared with a normal artery Full perfusion of the infarct vessel with normal flow Chesebro JH, Knatterud G, Roberts R, et al. Circulation 1987;76: PMID:

9 MYOCARDIAL BLUSH GRADES DEFINED Myocardial Blush Grades Grade 0 (MBG- 0) Failure of dye to enter the microvasculature. Either minimal or no ground glass appearance ( blush ) or opacification of the myocardium in the distribution of the culprit artery indicating lack of tissue-level perfusion. Grade 1 (MBG-1) Grade 2 (MBG- 2) Grade 3 (MBG- 3) Dye slowly enters but fails to exit the microvasculature. There is the ground glass appearance ( blush ) or opacification of the myocardium in the distribution of the culprit lesion that fails to clear from the microvasculature, and dye staining is present on the next injection (approximately 30 seconds between injections). Delayed entry and exit of dye from the microvasculature. There is the ground glass appearance ( blush ) or opacification of the myocardium in the distribution of the culprit lesion that is strongly persistent at the end of the washout phase (i.e., dye is strongly persistent after three cardiac cycles of the washout phase and either does not or only minimally diminishes in intensity during washout). Normal entry and exit of dye from the microvasculature. There is the ground glass appearance ( blush ) or opacification of the myocardium in the distribution of the culprit lesion that clears normally and is either gone or only mildly/moderately persistent at the end of the washout phase (i.e., dye is gone or is mildly/moderately persistent after three cardiac cycles of the washout phase and noticeably diminishes in intensity during the washout phase), similar to that in an uninvolved artery. Blush that is of only mild intensity throughout the washout phase but fades minimally is also classified as grade 3. van 't Hof AW, Liem A, Suryapranata H, et al. Circulation 1998;97: PMID:

10 Αγγειογραφικός ορισμός του φαινομένου Αποτελεί την παρουσία ενδοστεφανιαίας ροής TIMI 2 σε απουσία στένωσης, θρόμβωσης, διαχωρισμού ή αγγειόσπασμου του επικαρδιακού αγγείου.

11 Επικαρδιακή επαναγγείωση= μυοκαρδιακή επαναιμάτωση; No-reflow phenomenon The No-reflow is a dissociation between epicardial artery patency and myocardial perfusion

12 Where is the problem??? TIMI 3 FLOW Myocardial perfusion 16% of TIMI 3 flow post ppci have no-reflow as shown by cardiac MRI (infarct extension) *Ito et al. Circulation NO REFLOW = MICROVASCULAR OBSTRUCTION (MVO) Microvasculature <200µm

13 %age of optimal reperfusion, CADILLAC TRIAL 100 patients with STEMI treated by PPCI Evaluation of post procedural TIMI flow 1 pt with TIMI pts with TIMI 2 93 patients with TIMI 3 Evaluation of post procedural MBG Evaluation of post procedural STR> 70% 49 patients with TIMI 3 and MBG 2 or 3 35 patients with TIMI 3 and MBG 2 or 3 and STR>70 % 44 pts with MBG 0/1 14 pts with STR < 70%

14 Ποιοι είναι οι λόγοι που η βατότητα των επικαρδιακών αρτηριών δε μεταφράζεται σε αυξημένη ιστική αιμάτωση του μυοκαρδίου;

15 Figure 2. A, Schematic representation of pathophysiological mechanisms that may contribute to reperfusion no reflow in the setting of primary angioplasty for AMI. The vasculature within the necrotic zone is subjected to additional injury after reperfusion. Ronen Jaffe et al. Circulation. 2008;117: Copyright American Heart Association, Inc. All rights reserved.

16 Παθοφυσιολογία In humans, no-reflow is caused by the variable combination of 4 pathogenetic components: 1. Distal Atherothrombotic Embolization 2. Ischemic Injury 3. Reperfusion Injury 4. Susceptibility Of Coronary Microcirculation To Injury Distal embolization Reperfusion injury Ischemic injury Individual susceptibility J Am Coll Cardiol. 2009;54(4):

17 Περιφερικός Θρομβοεμβολισμός (1) Distal embolization Emboli of different sizes can originate from epicardial coronary thrombus and fissured atherosclerotic plaques, in particular during PPCI. Experimental observations have shown, that myocardial blood flow decreases irreversibly, when microspheres obstruct more than 50 % of coronary capillaries.

18 Περιφερικός Θρομβοεμβολισμός (2) Also occurs during elective PCI, especially in Vein Grafts Angioplasties. Strict correlation between microemboli and Troponin I elevation. Contributes in Inflammatory Reaction and Contractile Dysfunction. Induces Vasoconstriction, as confirmed by high serotonin levels.

19 Ισχαιμική Βλάβη No-Reflow area gets swollen. Certain morphological changes are seen that results to no reflow phenomenon The capillary endothelium damaged Areas of regional swelling with intraluminal protrusions, that in some plug the capillary lumen. Cellular edema compressing the capillaries Cell contracture in the ischemic zone also may contribute to the microvascular compression.

20 Βλάβη Επαναιμάτωσης Massive infiltration of coronary microcirculation by neutrophils and platelets at the time of reperfusion Subsequent adhesion at the endothelial surface and migration in the surrounding tissue Release of oxygen free radicals, proteolytic enzymes and proinflammatory mediators Tissue and endothelial damage Finally vasoconstrictors released by damaged endothelial cells, neutrophils and platelets Sustained vasoconstriction of coronary microcirculation. Neutrophils also form aggregates with platelets, that plug capillaries thus mechanically blocking flow

21 Ενδομυοκαρδιακή αιμορραγία Σοβαρή μορφή μικροαγγειακής απόφραξης, μέσω της ενδοθηλιακής καταστροφής και της συλλογής ερυθρών αιμοσφαιρίων στον εξωκυττάριο χώρο Πολυπαραγοντικό φαινόμενο (χρόνος ισχαιμίας, παράπλευρη ροή, ισχαιμικό preconditioning) Επεκτείνεται για ώρες πέραν της επαναγγείωσης Συνδέεται με την έκταση του εμφράγματος

22 Individual susceptibility to No-reflow Ατομική Ευαισθησία στη μη επαναρροή Diabetes and acute hyper-glycaemia Timmer et al, AJC, 2005 Iwakura et al, JACC, 2003

23 Individual susceptibility to No-reflow Ατομική Ευαισθησία στη μη επαναρροή Hypercholesterolemia Golino et al, Circulation, 1987 Iwakura et al, EHJ, 2006

24 Individual susceptibility to No-reflow Ατομική Ευαισθησία στη μη επαναρροή Prior drug therapy Niccoli et al, AJC, 2010

25 Individual susceptibility to No-reflow Ατομική Ευαισθησία στη μη επαναρροή Pre-infarction angina Karila-Cohen et al, EHJ, 1999

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28 Τύποι φαινομένου μη επαναρροής Μόνιμο Result of anatomical irreversible changes of coronary microcirculation Undergo unfavorable LV remodeling Παροδικό Result of functional & thus reversible changes of microcirculation Maintain their left ventricle volumes unchanged over time

29 CLASSIFICATION OF NO-REFLOW MYOCARDIAL INFARCTION REPERFUSION NO-REFOW Definition no-reflow in the setting of pharmacological and/or mechanical revascularization for acute myocardial infarction INTERVENTIONAL NO REFLOW Definition no-reflow during percutaneous coronary interventions especially rotational atherectomy, vein graft interventions

30 CLASSIFICATION Reperfusion No-Reflow Occurs in setting of ppci May be asymptomatic May present clinically with continued chest pain and ST elevation Preceded by ischemic cell injury Confined to the irreversibly damaged necrotic zone May be exacerbated at the time of reperfusion An independent predictor of adverse clinical outcome (heart failure, mortality) Interventional No-Reflow Follows non-infarct PCI Clinically is typically sudden in onset Presenting as acute ischemia with new onset chest pain and ECG changes May resolve over the course of several minutes Affected myocardium that was not subjected to prolonged ischemia before procedure Patients with interventional no-reflow have higher rates of mortality Interventional No-Reflow is unpredictable and uncommonly recognized in clinical practice

31 Κλινική εικόνα Θωρακικό άλγος ΗΚΓικές αλλοιώσεις Δυσλειτουργία αριστερής κοιλίας Αιμοδυναμική επιβάρυνση Αρρυθμίες Ασυμπτωματική;

32 Διάγνωση της μη επαναρροής Niccoli, EHJ, 2010

33 Πιθανότητα επιβίωσης με no reflow

34 Incidence (%) In-Hospital Clinical Outcomes Adjusted Odds Ratio for Mortality= 2.21, 95% CI , p<0.001 P< for each outcome

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36 No reflow occurs frequently during PCI in STEMI and is associated with reduced survival

37 Αγγειογραφικός ορισμός του φαινομένου Αποτελεί την παρουσία ενδοστεφανιαίας ροής TIMI 2 σε απουσία στένωσης, θρόμβωσης, διαχωρισμού ή αγγειόσπασμου του επικαρδιακού αγγείου. Κλινικές μελέτες έδειξαν ότι ροή TIMI 2 συνοδεύεται από χειρότερη πρόγνωση, όταν τη συγκρίνουμε με ροή TIMI 3 στο πέρας της αγγειοπλαστικής. Μάλιστα ροή η TIMI 2 δεν είναι ευνοϊκότερη από την ροή TIMI 1 ή 0 σχετικά με το αποτέλεσμα

38 Θεραπεία φαινομένου επαναρροής Δεν υπάρχουν μεγάλες τυχαιοποιημένες μελέτες Από τις υπάρχοντες μελέτες δεν προέκυψαν ασφαλή συμπεράσματα Επομένως, η θεραπεία δεν υπόκεινται σε σαφείς κατευθυντήριες οδηγίες

39 Θεραπεία ή Πρόληψη;

40 Πρόληψη του φαινομένου μη επαναρροής Πριν την έναρξη του ισχαιμικού πόνου Πριν την επαναιμάτωση Εντός του αιμοδυναμικού εργαστηρίου

41 Διαχείριση της ιδιαιτερότητας του ασθενούς για μικροκυκλοφοριακή βλάβη The DIGAMI (Diabetes Mellitus Insulin-Glucose Infusion in Acute Myocardial Infarction) study demonstrated that periprocedural reduction of blood glucose was associated with a reduction of infarct size Iwakura et al. have demonstrated that chronic statin therapy in patients with or without hypercholesterolemia is associated with lower prevalence of no-reflow and better functional recovery. Induction of ischemic pre-conditioning by drugs or nonpharmacologic stimuli such as remote ischemia of the arms Avoidance of substances potentially blocking pre-conditioning like sulfonylureas and high doses of alcohol

42 Διαχείριση της ισχαιμικής βλάβης Μειώνοντας το χρόνο από την έναρξη του συμπτώματος έως τη διάνοιξη του αγγείου. ( συνολικού ισχαιμικού χρόνου) Μειώνοντας την έκταση της ισχαιμίας, με φάρμακα που βελτιώνουν την μυοκαρδιακή αιμάτωση και περιορίζοντας την ανάγκη του μυοκαρδίου για οξυγόνο.

43 Predictors of pathogenic component of No-Flow and Therapeutic Implication Pathogenic Mechanism of No-Flow Predictor Therapeutic implication Distal embolization Thrombus burden Thrombus aspiration Ischemia Ischemia duration Reduction of coronary time Ischemia extent Reduction of oxygen consumption Reperfusion Neutrophil count Specific anti-neutrophil drug Individual susceptibility ET-1 levels TXA2 levels Mean platelet volume or reactivity Diabetes Acute hyperglycemia Hypercholestrolemia Lack of preconditioning ET-1 r antagonist TXA2 r antagonist Antiplatelet drugs Correction of hyperglycemia Correction of hyperglycemia Statin therapy Nicorandil ET= Endothelin; TXA2= Thromboxane A2 J Am Coll Cardiol. 2009;54(4):

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45 Θρομβοαναρρόφηση Αντικρουόμενα συμπεράσματα από τις μελέτες DEAR MI, REMEDIA, TAPAS vs TASTE, TOTAL Σύσταση για αναρρόφηση θρόμβου, σε επίπεδο PPCI, σε επιλεγμένους ασθενείς, με μεγάλο φορτίο θρόμβου, (Class iib, level of evidence A) ( 2014 ESC/EACTS guidelines on myocardial revascularization)

46 Φαρμακευτική αντιμετώπιση (1)

47 Φαρμακευτική αντιμετώπιση (2)

48 ABCIXIMAB RELAX-AMI study 2007 Upstream beneficial in reducing infarct size, no reflow incidence Thiele et al (CIRCULATION 2008) Intracoronary administration prior to PTCA beneficial CADILLAC 2002 No superior benefit to placebo in absence of thienopyridine loading

49 Tirofiban ONTIME 2 STUDY 2008 Infusion of tirofiban upstream beneficial Reduces no reflow incidence, infarct size on follow up

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51 Αδενοσίνη AMISTAD II Infarct Size Median LV Infarct Size (%) 40% p=0.122 p= % 20% 26% 23% 11% 10% 0% Placebo 50 μg 70 μg 57% reduction in median infarct size with 70 μg/kg/min x 3hrs, relative to placebo

52 Adenosine as an Adjunct to Reperfusion in the Treatment of Acute Myocardial Infarction post hoc study (n=2118) (AMISTAD-2 et al. EHJ 2006)

53 Αδενοσίνη & Νιτροπρωσικό νάτριο The ongoing multicentre, prospective, randomized REFLO-STEMI study will address this issue by comparing the benefits in terms of MVO and infarct size of intracoronary adenosine, sodium nitroprusside and standard therapy; primary endpoint of the trial is CMRI measured infarct size at 48 and 72 h after ppci

54 SUGGESTED INTRACORONARY DRUG ADMINISTRATION REGIMENS FOR PREVENTION/TREATMENT OF NO-REFLOW Verapamil Nicardipine Adenosine Sodium nitroprusside Nitroglycerin Nicorandil Boluses of µg up to four doses upto 1000µg 200µg bolus intracoronary Boluses of 24 µg up to four doses or 70µg/kg/mt infusion for 3 hours Boluses of 100 µg up to total of 1,000 µg Boluses of µg up to four doses Bolus of 2 mg intracoronary

55 NonInfarct PCI Distal embolic protection devices, Nicorandil *Jaffe et al. JACC 2010

56 Current guidelines suggested approach for no-reflow prevention ESC guidelines, EHJ, 2014

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58 Σας ευχαριστώ πολύ για την προσοχή σας

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61 Figure 1. Schematic illustrating the effect of duration of preceding myocardial ischemia on mechanism of no reflow (NR). Ronen Jaffe et al. Circulation. 2008;117: Copyright American Heart Association, Inc. All rights reserved.

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63 Prognosis and no-reflow Niccoli, JACC, 2009

64 Nicorandil is an adenosine triphosphatesensitive K + channel opener; this further vasodilator agent has proved in experimental models to reduce both infarct size and arrhythmias, but these results have not been reproduced in human trials

65 Also calcium channels blockers have been shown to improve microvascular dysfunction by regulating endothelial function and preventing microvessel spasm. Intracoronary verapamil demonstrated in STEMI patients a significant improvement in coronary artery flow measured by ctfc [67]. In the VAPOR trial intragraft verapamil administration has showed beneficial effect in patients undergoing vein grafts PCI [68]. A recent meta-analysis has confirmed that intracoronary verapamil injection, is able to prevent NR and reduce major adverse events in patients with acute coronary syndromes undergoing PCI [69].